A partitioned survival cost-effectiveness model informed by the final analyses from KEYNOTE-052 predicted long-term health and cost outcomes for cisplatin-ineligible patients with urothelial cancer with programmed death-ligand 1-positive tumors receiving either pembrolizumab or carboplatin plus gemcitabine. Over 20 years, treatment with pembrolizumab resulted in a mean gain of 2.58 life years and was shown to be cost-effective over carboplatin plus gemcitabine. Introduction: Pembrolizumab has been approved in the United States (US) for the first-line treatment of patients with advanced or metastatic urothelial carcinoma, who are ineligible for cisplatin-containing chemotherapy and with tumors expressing programmed death-ligand 1 (PD-L1) (Combined Positive Score ! 10), or ineligible for any platinumcontaining chemotherapy regardless of PD-L1 status. Long-term KEYNOTE-052 data continue to demonstrate pembrolizumab's meaningful, durable, and well-tolerated antitumor activity. This study evaluates the costeffectiveness of pembrolizumab versus carboplatin plus gemcitabine as first-line treatment for cisplatin-ineligible patients who have PD-L1epositive tumors from a US third-party healthcare payer's perspective. Patients and Methods: A partitioned survival model containing 3 health states (progression-free, progressed, and death) was developed. A simulated treatment comparison and a network meta-analysis were conducted to estimate the comparative efficacy of pembrolizumab versus carboplatin-based chemotherapy. Overall survival, progression-free survival, time on treatment, adverse events, and utilities were modeled using the final analyses of the KEYNOTE-052 trial and 4 studies for carboplatin plus gemcitabine. Cost data were estimated using US standard sources and real-world data. Deterministic, probabilistic, and scenario analyses were conducted to assess the robustness of the results. Results: Over 20 years, pembrolizumab resulted in a mean gain of 2.58 life-years, 2.01 quality-adjusted life-years, and additional costs of $158,561, leading to an incremental cost-effectiveness ratio of $78,925/qualityadjusted life-year compared with carboplatin plus gemcitabine. Conclusion: This study suggests that pembrolizumab is cost-effective compared with carboplatin plus gemcitabine as a first-line therapy for patients with advanced or metastatic urothelial carcinoma who are PD-L1epositive.